Programmed cell death ligand 1 (PD-L1) inhibition in tumor naïve mice is bone-sparing throughout the lifespan.

Authors

Madeline B Searcy, Gwenyth J Joseph, Jeremy F Kane, Laasya Challa, Hidenori Tanaka, Sasidhar Uppuganti, Jailyn A Smith, Eben L Rosenthal, David G Harrison, Jeffry S Nyman, Megan M Weivoda, Rachelle W Johnson

Published in

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. Jul 09, 2026. Epub Jul 09, 2026.

Abstract

Immune checkpoint inhibitors (ICIs) which target immune checkpoint proteins like programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have revolutionized cancer therapy. Skeletal toxicities are emerging immune-related adverse events for patients treated with ICIs, and PD-1 blockade in pre-clinical mouse models significantly reduces bone mass. However, the effect of PD-L1 inhibition on the bone throughout development is not well understood. We investigated the role of PD-L1 loss on bone microarchitecture with genetic PD-L1 knockout in myeloid cells using LysM-Cre;PD-L1Flox/Flox mice and pharmacologic inhibition with a PD-L1 neutralizing antibody in adult and aged mice. We report that neither PD-L1 deletion in myeloid cells nor inhibition with α-PD-L1 significantly impacts femoral trabecular bone microarchitecture; however, α-PD-L1 treatment increases vertebral trabecular bone volume. Additionally, PD-L1 blockade influences T cell expansion by decreasing naïve T cells and increasing effector memory T cells in the bone marrow, consistent with previous studies on the effects of PD-1 inhibition. The trabecular bone-sparing effect of PD-L1 inhibition is strikingly different from the bone loss observed with PD-1 blockade. Clinical studies are necessary and justified to determine if PD-L1 may be a less bone destructive alternative for cancer patients treated with ICIs who are at high risk of fracture.

PMID:
42424413
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.

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